Method for the sysnthesis of compounds of formula I and their uses thereof

ABSTRACT

This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, their use in treating human or animal disorders. The compounds of the invention are useful as modulators of the interaction between the receptor for advanced glycated end products (RAGE) and its ligands, such as advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, and for the management, treatment, control, or as an adjunct treatment for diseases in humans caused by RAGE. Such diseases or disease states include acute and chronic inflammation, the development of diabetic late complications such as increased vascular permeability, nephropathy, atherosclerosis, and retinopathy, the development of Alzheimer&#39;s disease, erectile dysfunction, and tumor invasion and metastasis.

This application is a continuation application of U.S. application Ser.No. 10/611,741, filed Jul. 1, 2003, which is a divisional application ofapplication Ser. No. 09/799,317, filed Mar. 5, 2001, now U.S. Pat. No.6,613,801, which claims the benefit of U.S. Provisional Application No.60/207,343, filed May 30, 2000.

FIELD OF THE INVENTION

This invention relates to compounds which are modulators of the receptorfor advanced glycated end products (RAGE) and interaction with itsligands such as advanced glycated end products (AGEs),S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, for the management,treatment, control, or as an adjunct treatment of diseases caused byRAGE.

BACKGROUND OF THE INVENTION

Incubation of proteins or lipids with aldose sugars results innonenzymatic glycation and oxidation of amino groups on proteins to formAmadori adducts. Over time, the adducts undergo additionalrearrangements, dehydrations, and cross-linking with other proteins toform complexes known as Advanced Glycosylation End Products (AGEs).Factors which promote formation of AGEs included delayed proteinturnover (e.g. as in amyloidoses), accumulation of macromolecules havinghigh lysine content, and high blood glucose levels (e.g. as in diabetes)(Hori et al., J. Biol. Chem. 270: 25752-761, (1995)). AGEs haveimplicated in a variety of disorders including complications associatedwith diabetes and normal aging.

AGEs display specific and saturable binding to cell surface receptors onendothelial cells of the microvasculature, monocytes and macrophages,smooth muscle cells, mesengial cells, and neurons. The Receptor forAdvanced Glycated Endproducts (RAGE) is a member of the immunoglobulinsuper family of cell surface molecules. The extracellular (N-terminal)domain of RAGE includes three immunoglobulin-type regions, one V(variable) type domain followed by two C-type (constant) domains (Neeperet al., J. Biol. Chem. 267:14998-15004 (1992). A single transmembranespanning domain and a short, highly charged cytosolic tail follow theextracellular domain. The N-terminal, extracellular domain can beisolated by proteolysis of RAGE to generate soluble RAGE (sRAGE)comprised of the V and C domains.

RAGE is expressed in most tissues, and in particular, is found incortical neurons during embryogenesis (Hori et al., J. Biol. Chem.270:25752-761 (1995)). Increased levels of RAGE are also found in agingtissues (Schleicher et al., J. Clin. Invest. 99 (3): 457-468 (1997)),and the diabetic retina, vasculature and kidney (Schmidt et al., NatureMed. 1: 1002-1004 (1995)). Activation of RAGE in different tissues andorgans leads to a number of pathophysiological consequences. RAGE hasbeen implicated in a variety of conditions including: acute and chronicinflammation (Hofmann et al., Cell 97:889-901 (1999)), the developmentof diabetic late complications such as increased vascular permeability(Wautier et al., J. Clin. Invest. 97:238-243 (1995)), nephropathy(Teillet et al., J. Am. Soc. Nephrol. 11:1488-1497 (2000)),atherosclerosis (Vlassara et. al., The Finnish Medical Society DUODECIM,Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al.;Diabetologia 42:603-607 (1999)). RAGE has also been implicated inAlzheimer's disease (Yan et al., Nature 382: 685-691, (1996)), erectiledysfunction, and in tumor invasion and metastasis (Taguchi et al.,Nature 405: 354-357, (2000)).

In addition to AGEs, other compounds can bind to, and modulate RAGE. Innormal development, RAGE interacts with amphoterin, a polypeptide whichmediates neurite outgrowth in cultured embryonic neurons (Hori et al.,1995). RAGE has also been shown to interact with EN-RAGE, a proteinhaving substantial similarity to calgranulin (Hofmann et al., Cell97:889-901 (1999)). RAGE has also been shown to interact with β-amyloid(Yan et al., Nature 389:589-595, (1997); Yan et al., Nature 382:685-691(1996); Yan et al., Proc. Natl. Acad. Sci., 94:5296-5301 (1997)).

Binding of ligands such as AGEs, S100/calgranulin/EN-RAGE, β-amyloid,CML (N^(ε)-Carboxymethyl lysine), and amphoterin to RAGE has been shownto modify expression of a variety of genes. For example, in many celltypes interaction between RAGE and its ligands generates oxidativestress, which thereby results in activation of the free radicalsensitive transcription factor NF-κB, and the activation of NF-κBregulated genes, such as the cytokines IL-1β, TNF-α, and the like. Inaddition, several other regulatory pathways, such as those involvingp21ras, MAP kinases, ERK1 and ERK2, have been shown to be activated bybinding of AGEs and other ligands to RAGE. In fact, transcription ofRAGE itself is regulated at least in part by NF-κB. Thus, an ascending,and often detrimental, spiral is fueled by a positive feedback loopinitiated by ligand binding. Antagonizing binding of physiologicalligands to RAGE, therefore, is our target for down-regulation of thepathophysiological changes brought about by excessive concentrations ofAGEs and other ligands for RAGE.

Thus, there is a need for the development of compounds that antagonizebinding of physiological ligands to the RAGE receptor.

SUMMARY OF THE INVENTION

This invention provides compounds which are useful as RAGE modulators.In a preferred embodiment, the present invention provides compounds ofFormula (I) as depicted below, to methods of their preparation,pharmaceutical compositions comprising the compounds and to their use intreating human or animal disorders.

The compounds of the invention are useful as modulators of theinteraction of the receptor for advanced glycated end products (RAGE)with its ligands such as advanced glycated end products (AGEs),S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, and thus are usefulfor the management, treatment, control, and/or as an adjunct treatmentof diseases in humans caused by RAGE. Such diseases or disease statesinclude acute and chronic inflammation, the development of diabetic latecomplications such as increased vascular permeability, nephropathy,atherosclerosis, and retinopathy, the development of Alzheimer'sdisease, erectile dysfunction, and tumor invasion and metastasis.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention provides a compound comprisingat least one moiety of the formula

wherein L₁ and L₂ are each a hydrocarbon group of from 1 to 6 carbons ora direct bond, and Aryl₁ and Aryl₂ are aryl, wherein each of Aryl₁ andAryl₂ are substituted by at least one lipophilic group. In a preferredembodiment, the lipophilic group is selected from C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylaryl, or C₁₋₆ alkoxyaryl. We have found such compoundsto be useful in the modulation, preferably in the inhibition of theinteraction of RAGE with its physiological ligands, as will be discussedin more detail below.

In a second aspect, the present invention provides compounds of Formula(I):

whereinR₁ and R₂ are independently selected from

a) —H;

b) —C₁₋₆ alkyl;

c) -aryl;

d) —C₁₋₆ alkylaryl;

e) —C(O)—O—C₁₋₆ alkyl;

f) —C(O)—O—C₁₋₆ alkylaryl;

g) —C(O)—NH—C₁₋₆ alkyl;

h) —C(O)—NH—C₁₋₆ alkylaryl;

i) —SO₂—C₁₋₆ alkyl;

j) —SO₂—C₁₋₆ alkylaryl;

k) —SO₂-aryl;

l) —SO₂—NH—C₁₋₆ alkyl;

m) —SO₂—NH—C₁₋₆ alkylaryl;

n)

o) —C(O)—C₁₋₆ alkyl; and

p) —C(O)—C₁₋₆ alkylaryl;

R₃ is selected from

a) —C₁₋₆ alkyl;

b) -aryl; and

c) —C₁₋₆ alkylaryl;

R₄ is selected from

a) —C₁₋₆ alkylaryl;

b) —C₁₋₆ alkoxyaryl; and

c) -aryl;

R₅ and R₆ are independently selected from the group consisting ofhydrogen, C₁-C₆ alkyl, C₁-C₆ alkylaryl, and aryl; and wherein

the aryl and/or alkyl group(s) in R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉,R₁₀, R₁₈, R₁₉, and R₂₀ may be optionally substituted 1-4 times with asubstituent group, wherein said substituent group(s) or the termsubstituted refers to groups selected from the group consisting of:

a) —H;

b) —Y—C₁₋₆ alkyl;

-   -   —Y-aryl;    -   —Y—C-₁₋₆ alkylaryl;    -   —Y—C₁₋₆-alkyl-NR₇R₈; and    -   —Y—C₁₋₆-alkyl-W—R₂₀;        -   wherein Y and W are, independently selected from the group            consisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—,            —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,            —NHSO₂NH—, —O—CO—,

c) halogen, hydroxyl, cyano, carbamoyl, or carboxyl; and

R₁₈ and R₁₉ are independently selected from the group consisting ofaryl, C₁-C₆ alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl;

R₂₀ is selected from the group consisting of aryl, C₁-C₆ alkyl, andC₁-C₆ alkylaryl;

R₇, R₈, R₉ and R₁₀ are independently selected from the group consistingof hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; and wherein

R₇ and R₈ may be taken together to form a ring having the formula—(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇ and R₈are attached, and/or R₅ and R₆ may, independently, be taken together toform a ring having the formula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to thenitrogen atoms to which R₅ and R₆ are attached, wherein m and n are,independently, 1, 2, 3, or 4; X is selected from the group consisting of—CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,—NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In the compounds of Formula (I), the various functional groupsrepresented should be understood to have a point of attachment at thefunctional group having the hyphen. In other words, in the case of —C₁₋₆alkylaryl, it should be understood that the point of attachment is thealkyl group; an example would be benzyl. In the case of a group such as—C(O)—NH—C₁₋₆ alkylaryl, the point of attachment is the carbonyl carbon.

In a preferred embodiment of this aspect of the invention, the compoundsof Formula (I) include those wherein:

R₁ is hydrogen;

R₂ is selected from

a) —H;

b) —C₁₋₆ alkyl;

c) —C₁₋₆ alkylaryl;

d) —C(O)—O—C₁₋₆ alkyl;

e) —C(O)—NH—C₁₋₆ alkyl;

f) —C(O)—NH—C₁₋₆ alkylaryl;

g) —SO₂—C₁₋₆ alkyl;

h) —SO₂—C₁₋₆ alkylaryl;

i) —SO₂—NH—C₁₋₆ alkyl; and

j)

k) —C(O)—C₁₋₆ alkyl;

l) —C(O)—C₁₋₆ alkylaryl;

R₃ is selected from

a) —C₁₋₄ alkylaryl; and

R₄ is selected from

a) —C₁₋₄ alkylaryl; and

b) -aryl;

and wherein the aryl group in R₁, R₂, R₃ and R₄ is optionallysubstituted 1-4 times with a substituent group, wherein said substituentgroup(s) or the term substituted refers to groups selected from thegroup consisting of:

a) —H;

b) —Y—C₁₋₆ alkyl;

—Y-aryl;

—Y—C₁₋₆ alkylaryl;

—Y—C₁₋₆-alkyl-NR₇R₈; and

—Y—C₁₋₆—W—R₂₀;

-   -   wherein Y and W are, independently selected from the group        consisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—,        —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

c) halogen, hydroxyl, carbamoyl, and carboxyl;

-   -   R₁₈ and R₁₉ are selected from the group consisting of aryl,        C₁-C₆ alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆        alkoxyaryl;

-   R₂₀ is selected from the group consisting of aryl, C₁-C₆ alkyl, or    C₁-C₆ alkylaryl, and wherein    -   R₇ and R₈ are selected from the group consisting of hydrogen,        aryl, C₁-C₆ alkyl, or C₁-C₆ alkylaryl; and wherein        R₇ and R₈ may be taken together to form a ring having the        formula —(CH₂)_(m)—X—(CH₂)_(n)-bonded to the nitrogen atom to        which R₇ and R₈ are attached, and/or R₅ and R₆ may,        independently, be taken together to form a ring having the        formula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atoms to        which R₅ and R₆ are attached, wherein m, n, and X are as defined        above.

In a further preferred embodiment, the R₃ groups above include C₁₋₃alkylaryl, said aryl optionally substituted by substituted 1-4 timeswith a substituent group, wherein said substituent group(s) or the termsubstituted refers to groups selected from the group consisting of:

-   -   —Y—C₁₋₆ alkyl;    -   —Y-aryl;    -   —Y—C-₁₋₆ alkylaryl;    -   —Y—C₁₋₆-alkyl-NR₇R₈; and    -   —Y—C₁₋₆-alkyl-W—R₂₀;        -   wherein Y and W are, independently selected from the group            consisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—,            —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,            —NHSO₂NH—, —O—CO—,

A further preferred embodiment is the embodiment referred to above,wherein wherein aryl is phenyl or napthyl, optionally substituted byC₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylaryl, or C₁₋₆ alkoxyaryl.

Also included within the scope of the invention are the individualenantiomers of the compounds represented by Formula (I) above as well asany wholly or partially racemic mixtures thereof. The present inventionalso covers the individual enantiomers of the compounds represented byformula above as mixtures with diastereoisomers thereof in which one ormore stereocenters are inverted.

Compounds of the present invention which are preferred for their highbiological activity are listed by name below in Table 1. TABLE 1 Ex- am-ple Chemical Name 1 (R)-3-(2-Naphthyl)-2-aminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 2(R)-3-(2-Naphthyl)-2-aminopropionic Acid 4-Methoxycarbonyl-2-butoxyaniline Amide Hydrochloride 3(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 4(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 5(R)-3-(2-Naphthyl)-2-methylaminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 6(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-Methoxycarbonyl-2-hydroxyaniline Amide 7(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-tert-Butoxycarbonyl-2-tert-butoxyaniline Amide 8(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-isobutoxyaniline Amide 9(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-isobutoxyaniline Amide Dihydrochloride 10(R)-3-Phenyl-2-tert-butoxycarbonylaminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 11(R)-3-Phenyl-2-aminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 12(R)-3-(2-Naphthyl)-2-guanidinylpropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide Dihydrochloride 13(R)-3-(4-Benzyloxyphenyl)-2-isopropylaminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 14(R)-3-(4-Benzyloxyphenyl)-2-benzylaminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 15(R)-3-(4-Benzyloxyphenyl)-2-methanesulfonylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 16(R)-3-(4-Benzyloxyphenyl)-2-phenylsulfonylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 17(R)-3-(4-Benzyloxyphenyl)-2-ethylcarbamoylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 18(R)-3-(4-Benzyloxyphenyl)-2-tert-butylcarbamoylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 19(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-Diethylaminoethoxy-2-diethylaminoethoxyaniline Amide 20(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-Diethylaminoethoxy-2-diethylaminoethoxyaniline Amide Trihydrochloride 21(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-(3-Diethylamino-1-propoxy)-2-(3-diethylamino-1- propoxy)aniline Amide22 (R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-(3-Diethylamino-1-propoxy)-2-(3-diethylamino-1-propoxyaniline AmideTrihydrochloride 23(R)-3-(4-Benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic Acid4-Diethylaminoethoxycarbonyl-2-(2-furylmethoxy)aniline Amide 24(R)-3-(4-Benzyloxyphenyl)-2-aminopropionic Acid 4-Diethylaminoethoxycarbonyl)-2-(2-furylmethoxy)aniline AmideDihydrochloride 25 (R)-3-(2-Naphthyl)-2-acetylaminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide 26(R)-3-(4-Benzyloxyphenyl)-2-acetylaminopropionic Acid 4-Diethylaminoethoxycarbonyl-2-butoxyaniline Amide

Accordingly, in a further embodiment of the invention, there is providedthe above compounds, or the free amine, free acid, solvate, prodrug, orpharmaceutically acceptable salt thereof.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having the number of specified carbon atoms. Examples of“alkyl” as used herein include, but are not limited to, methyl, n-butyl,n-pentyl, isobutyl, and isopropyl, and the like.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, and the like.

As used herein, the term “aryl” refers to a five—to seven—memberedaromatic ring, or to an optionally substituted benzene ring system,optionally containing one or more nitrogen, oxygen, or sulfurheteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides arepermissible substitutions. Such a ring may be fused to one or morefive—to seven—membered aromatic rings optionally containing one or morenitrogen, oxygen, or sulfur heteroatoms. Preferred aryl groups includephenyl, biphenyl, 2-naphthyl, 1-naphthyl, phenanthryl, 1-anthracenyl,pyridyl, furyl, furanyl, thiophenyl, indolyl, isothiazolyl, imidazolyl,benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,benzofuryl, isobenzofuryl, benzothienyl, benzindoyl, pyrazolyl,isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl,benzothiazolyl, benzoxazolyl, and the like. In this regard, especiallypreferred aryl groups include phenyl, 2-naphthyl, 1-naphthyl, biphenyl,and like ring systems optionally substituted by tert-butyloxy,benzyloxy, n-butyloxy, ispropyloxy, and phenoxy.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

As used herein, the chemical structure terms “contain” or “containing”refer to in-line substitutions at any position along the above definedsubstituent at one or more of any of O, S, SO, SO₂, N, or N-alkyl,including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—, —CH₂—NH—CH₃ and soforth.

As used herein, the term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula (I)) and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Solvents may be, by way of example, water, ethanol, or acetic acid.

As used herein, the term “biohydrolyzable ester” is an ester of a drugsubstance (in this invention, a compound of formula (I)) which either a)does not interfere with the biological activity of the parent substancebut confers on that substance advantageous properties in vivo such asduration of action, onset of action, and the like, or b) is biologicallyinactive but is readily converted in vivo by the subject to thebiologically active principle. The advantage is that, for example, thebiohydrolyzable ester is orally absorbed from the gut and is transformedto (I) in plasma. Many examples of such are known in the art and includeby way of example lower alkyl esters (e.g., C₁-C₄), lower acyloxyalkylesters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkylacylamino alkyl esters, and choline esters.

As used herein, the term “biohydrolyzable amide” is an amide of a drugsubstance (in this invention, a compound of general formula (I)) whicheither a) does not interfere with the biological activity of the parentsubstance but confers on that substance advantageous properties in vivosuch as duration of action, onset of action, and the like, or b) isbiologically inactive but is readily converted in vivo by the subject tothe biologically active principle. The advantage is that, for example,the biohydrolyzable amide is orally absorbed from the gut and istransformed to (I) in plasma. Many examples of such are known in the artand include by way of example lower alkyl amides, α-amino acid amides,alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

As used herein, the term “prodrug” includes biohydrolyzable amides andbiohydrolyzable esters and also encompasses a) compounds in which thebiohydrolyzable functionality in such a prodrug is encompassed in thecompound of formula (I): for example, the lactam formed by a carboxylicgroup in R₂ and an amine in R₄, and b) compounds which may be oxidizedor reduced biologically at a given functional group to yield drugsubstances of formula (I). Examples of these functional groups include,but are not limited to, 1,4-dihydropyridine,N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, andthe like. The term “pharmacologically effective amount” shall mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, animal or human that is being sought bya researcher or clinician. This amount can be a therapeuticallyeffective amount.

Whenever the terms “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall beinterpreted as including those limitations given above for “alkyl” and“aryl”. Alkyl substituents shall be recognized as being functionallyequivalent to those having one or more degrees of unsaturation.Designated numbers of carbon atoms (e.g. C₁₋₆) shall refer independentlyto the number of carbon atoms in an alkyl moiety or to the alkyl portionof a larger substituent in which the term “alkyl” appears as its prefixroot. Similarly, the term “C₂-C₈ alkenyl” and C₂-C₈ alkynyl” refer togroups having from 2 to 8 carbon atoms and at least one carbon-carbondouble bond or carbon-carbon triple bond, respectively. The term“lower”, for example in relation to “lower alkyl” refers to a C₁₋₆ alkylgroup.

As used herein, the term “oxo” shall refer to the substituent ═O.

As used herein, the term “halogen” or “halo” shall include iodine,bromine, chlorine and fluorine.

As used herein, the term “mercapto” shall refer to the substituent —SH.

As used herein, the term “carboxy” shall refer to the substituent —COOH.

As used herein, the term “cyano” shall refer to the substituent —CN.

As used herein, the term “aminosulfonyl” shall refer to the substituent—SO₂NH₂.

As used herein, the term “carbamoyl” shall refer to the substituent—C(O)NH₂.

The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds ofFormula (I) along with methods for the preparation of compounds ofFormula (I).

A suitably protected alpha-amino acid (1), where PG is an amineprotecting group such as tert-butoxycarbonyl, is treated with an aminein the presence of a coupling reagent such as but not limited todiisopropyl carbodiimide (DIC) to form the amide (2). The α-amino groupin (2) is then deprotected, employing a strong acid such as hydrogenchloride for the case where PG is tert-butoxycarbonyl, to afford thefree amine (3) either as the free base or as a salt (Scheme 1). Asuitably protected alpha-amino acid (1), where PG is an amine protectinggroup such as tert-butoxycarbonyl, is treated with an amine in thepresence of a coupling reagent such as but not limited to diisopropylcarbodiimide (DIC) to form the amide (2). The α-amino group in (2) isthen deprotected, employing a strong acid such as hydrogen chloride forthe case where PG is tert-butoxycarbonyl, to afford the free amine (3)either as the free base or as a salt (Scheme 1).

To further derivatize the amino group of compound (3), the free aminocompound, or the suitable salt thereof may be treated with an aldehydeor ketone R₁₂C(O)R₁₁ in the presence of a reducing agent such as sodiumcyanoborohydride or sodium triacetoxyborohydride to afford compound (4),where R₁₂ and R₁₁ are defined such that R₂ in (4) conforms to thespecifications for Formula (I). Alternately, the amine compound (3) maybe treated with tertiary amine base such as DIEA and a molar equvalentamount (or slight excess) of an alkylating agent of general structureR₂-Z, where Z is is a nucleofugal group such as bromine, to form thesecondary amine compound (4) (Scheme 2). Amine (3) may be treated with atertiary amine base such as DIEA and 2 molar equivalents (or slightexcess) of an alkylating agent of general structure R₂-Z, where Z is isa nucleofugal group such as bromine, to form the amine compound (5).Alternately, the amine compound (3) may be treated with an electrondeficient olefinic compound such as but not limited to ethyl acrylate,to afford the adduct intermediate (6). Compound (6) may be manipulated,employing methods known in the art such as hydride reduction, intransforming such an adduct to compounds of general structure (4).

To further derivatize the amino group of compound (3), the free aminocompound, or the suitable salt thereof may be treated with a sulfonylchloride such as benzenesulfonyl chloride to form the sulfonamide (7)(Scheme 3), where R₁₄ is C₁₋₆ alkyl, C₁₋₆ alkylaryl, or aryl.Alternately, an amine R₁₅—NH₂ may be treated with sulfuryl chloride andthe intermediate then treated with (2) to afford the sulfonylurea (7)where R₁₄ is —NH—C₁₋₆ alkyl or —NH—C₁₋₆ alkylaryl.

To further derivatize the amino group of compound (3), the free aminocompound, or the suitable salt thereof may be treated with an isocyanateR₁₅NCO in the presence or absence of a tertiary amine base such as TEAto form the urea (8) (Scheme 4), where R₁₅ is —C₁₋₆ alkyl or —C₁₋₆alkylaryl and Q is NH. Alternately, compound (3) may be treated withR₁₅O—C(O)Cl and a tertiary amine base such as TEA to afford compound (8)where R₁₅ is —C₁₋₆ alkyl or —C₁₋₆ alkylaryl and Q is O.

Compound (9) may be treated with triphenyl phosphine, either diisopropylazodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) and analcohol R₁₆—OH to form the compound (10) (Scheme 5), after removal ofthe protecting group PG. R₁₆ is —C₁₋₆ alkyl, —C₁₋₆ alkylaryl, —C₁₋₆alkyl-OSi(C₁₋₆ alkyl)₃, —C₁₋₆ alkyl-OSi(C₁₋₆ alkylaryl)₃, or —C₁₋₆alkyl-NR₈R₉ (provided that neither R₈ nor R₉ are hydrogen). PG may be,for example, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

Compound (3) or a suitable salt thereof may be treated with a acidanhydride (R₁₇—CO)₂O and a base such as TEA in the presence or absenceof pyridine or DMAP to afford compound (11) (Scheme 6). The substituentR₁₇ may be chosen such that the group R₁₇—C(O)— is as specified for R₂in Formula (I). Alternately, compound (3) may be treated with the acidchloride R₁₇—COCl and an tertiary amine base such as TEA in the presenceor absence of pyridine or DMAP to afford compound (11). Alternately,compound (3) may be treated with the carboxylic acid R₁₇—CO₂H and acarbodiimide reagent (i.e., a “coupling reagent”) such as EDC, DIC, orDCC in the presence or absence of HOBt to provide compound (11).

Compound (3) or a suitable salt thereof may be treated (Scheme 7) withan activated amidine reagent such as N,N′-bis-BOC-1-guanylpyrazole or3,5-dimethylpyrazole-1-carboxamidine nitrate in the presence of atertiary organic base such as TEA to generate the guanidine compound.Guanidine substituent protecting groups may be removed. For example,where N,N′-bis-BOC-1-guanylpyrazole is employed, the BOC groups of theadduct may be removed with a strong acid such as hydrogen chloride toafford the free guanidine compound (12), where R₅ and R₆ are as definedfor Formula (I).

General Experimental

LC-MS data was obtained using gradient elution on a Waters 600controller equipped with a 2487 dual wavelength detector and a LeapTechnologies HTS PAL Autosampler using an YMC Combiscreen ODS-A 50×4.6mm column. A three minute gradient was run from 25% B (97.5%acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5%acetonitrile, 0.05% TFA) to 100% B. The MS was a Micromass ZMDinstrument. All data was obtained in the positive mode unless otherwisenoted. ¹H NMR data was obtained on a Varian 300 MHz spectrometer.

Abbreviations used in the Examples are as follows:

APCI=atmospheric pressure chemical ionization

BOC=tert-butoxycarbonyl

BOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphoniumhexafluorophosphate

d=day

DIAD=diisopropyl azodicarboxylate

DCC=dicyclohexylcarbodiimide

DCM=dichloromethane

DIEA=diisopropylethylamine

DMF=N,N-dimethylformamide

DMPU=1,3-dimethypropylene urea

DMSO=dimethylsulfoxide

EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride

EDTA=ethylenediamine tetraacetic acid

ELISA=enzyme—linked immunosorbent assay

ESI=electrospray ionization

ether=diethyl ether

EtOAc=ethyl acetate

FBS=fetal bovine serum

g=gram

h=hour

HBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

HMPA=hexamethylphosphoric triamide

HOBt=1-hydroxybenzotriazole

Hz=hertz

i.v.=intravenous

kD=kiloDalton

L=liter

LAH=lithium aluminum hydride

LDA=lithium diisopropylamide

LPS=lipopolysaccharide

M=molar

m/z=mass to charge ratio

mbar=millibar

MeOH=methanol

mg=milligram

min=minute

mL=milliliter

mM=millimolar

mmol=millimole

mol=mole

mp=melting point

MS=mass spectrometry

N=normal

NMM=N-methylmorpholine, 4-methylmorpholine

NMR=nuclear magnetic resonance spectroscopy

p.o.=per oral

PBS=phosphate buffered saline solution

PMA=phorbol myristate acetate

ppm=parts per million

psi=pounds per square inch

R_(f)=relative TLC mobility

rt=room temperature

s.c.=subcutaneous

SPA=scintillation proximity assay

TEA=triethylamine

TFA=trifluoroacetic acid

THF=tetrahydrofuran

THP=tetrahydropyranyl

TLC=thin layer chromatography

Tr=retention time

The following compounds are synthesized according to the Schemes.

EXAMPLE 1

To a solution of BOC-2-naphthyl-(D)-alanine (3.15 g) in CH₂Cl₂ (40 mL),HOBt (1.35 g) and DCC (2.2 g) were added at rt under nitrogenatmosphere. After 2 h NEt₃ (2.79 mL) and4-diethylaminoethoxycarbonyl-2-butoxyaniline hydrochloride (3.8 g) wereadded followed by DMAP (122 mg). The reaction mixture is then stirred atrt for 3 d and filtered to remove dicyclohexylurea. The filtrate isconcentrated and purified by silica gel column chromatography to afford4.8 g of the amide Intermediate 1A. 1H NMR (CDCl3): 8.50 (d, 1H), 8.27(br s, 1H), 7.55-7.85 (m, 5H), 7.25-7.45 (m, 5H), 5.15 (br s, 1H), 4.60(br s, 1H), 4.38 (t, 2H), 3.6-3.9 (m, 2H), 3.30 (d, 2H), 2.82 (t, 2H),2.60 (q, 4H), 1.2-1.8 (m, 10H), 1.10 (t, 6H).

MS: m/z 606 (M+H)⁺

120 mg of Intermediate 1A obtained above is stirred in 4 M HCl indioxane (2 mL) for 3 h. Solvent is then removed in vacuo and the residueobtained is treated with ether and stirred. The ether is decanted offand the ether wash is repeated twice more. The product is then driedunder vacuum to afford a pale yellow solid (90 mg), Example 1.

LC: T_(r) 1.53; MS: 506 (M+H)⁺

EXAMPLE 2

Example 1 (115 mg) is dissolved in anhydrous methanol (5 mL) and treatedwith 1 M KOH in methanol (25 μL). The reaction mixture is stirredovernight at rt and added with 2 drops of acetic acid and stirred.Solvent is then removed in vacuo and the residue obtained is purified bysilica gel column chromatography to yield the methyl ester Intermediate2A (65 mg).

NMR (acetone-d6): 9.10 (br s, 1H), 8.42 (d, 2H), 7.20-7.80 (m, 7H), 6.78(br d, 1 h), 4.50 (br m, 1H), 4.0 (br m, 2H), 3.76 (s, 3H), 3.20 (dd,1H), 2.9-3.2 (m, 4H), 1.22 (q, 2H), 1.20 (s, 9H), 0.90 (t, 3H).

MS: m/z 521 (M+H)⁺

Intermediate 2A is dissolved in 4M HCl in dioxane (2 mL) and stirred atrt for 3 h. Product is isolated as for Example 1 to afford Example 2 asa fluffy white solid (50 mg).

MS: m/z 421 (M+H)⁺

EXAMPLE 3

To a solution of BOC-D-Tyr(Bzl)-OH (1.11 g) in CH₂Cl₂ (15 mL), HOBT (406mg) and DCC (681 mg) were added at rt. After 2 h TEA (840 μL) and4-diethylaminoethoxycarbonyl-2-butoxyaniline hydrochloride (1.04 g) wereadded followed by DMAP (36 mg). The reaction mixture is then stirred atrt for 3 d and filtered to remove dicyclohexylurea. The filtrate isconcentrated and purified on a silica gel column chromatography toafford 1.2 g of Example 3.

LC: T_(r) 2.18; MS: m/z 662 (M+H)⁺

EXAMPLE 4

165 mg of Example 3 is stirred in 4M HCl in dioxane (2 mL) for 3 h.Product is isolated as for Example 1 to afford Example 4 as a paleyellow solid (105 mg).

LC: T_(r) 1.75; MS: m/z 562(M+H)⁺

EXAMPLE 5

BOC-(2-naphthyl)-D-alanine (946 mg) is dissolved in anhydrous THF at rt,added with methyl iodide (1.5 mL) and cooled to 0° C. Solid NaH (400 mg;60% dispersion in oil) is slowly added to it and the reaction is allowedto proceed overnight with gradual warming up to rt. After 24 h thereaction mixture is diluted with a mixture of EtOAc and cold water andstirred. The contents were then shaken a separatory funnel and thelayers were separated. The aqueous layer is then extracted with EtOAc.The organic extracts were combined, ished with water and brine and driedover anhydrous sodium sulfate. Solvent is removed in vacuo and theresidue obtained is purified by silica gel solumn chromatography toafford the acid Intermediate 5A (630 mg).

MS: m/z 230 (M+H)⁺

To a solution of Intermediate 5A obtained as above (616 mg) in CH₂Cl₂(10 mL), HOBt (303 mg) and DCC (463 mg) were added at rt under nitrogenatmosphere. After 2 h triethylamine (651 μL) and4-diethylaminoethoxycarbonyl-2-butoxyaniline hydrochloride (645 mg) wereadded followed by DMAP (36 mg). The reaction mixture is then stirred atrt for 4 d and filtered to remove dicyclohexylurea. The filtrate isconcentrated and purified on a silica gel column chromatography toafford Intermediate 5B (220 mg).

LC: T_(r) 2.45 min; MS: m/z 620 (M+H)⁺

Intermediate 5B is then dissolved in 4M HCl in dioxane (4 mL) for 3 h.Product is isolated as for Example 1 to afford Example 5 (160 mg).

MS: m/z 520 (M+H)⁺

EXAMPLE 6

BOC-D-Tyr(Bzl)-OH (4.46 g, 12.0 mmol) is suspended in 50 mL of DCM andto this is added DCC (2.72 g, 13.20 mmol) and HOBt (1.62 g, 12.01 mmol)and the mixture stirred under nitrogen for 2 h. Triethylamine (3.3 mL)is added followed by 4-amino-3-hydroxy benzoic acid methyl ester (2.67g, 13.20 mmol). The mixture is stirred for 4 d. The reaction mixture isfiltered and the solid residue washed with DCM. The filtrate is thenwashed with 5% Na₂CO₃ solution (2×50 mL) followed by brine solution. Theorganic extract is dried over Na₂SO₄, filtered and concentrated andpurified by flash chromatography on silica gel eluted with EtOAc/hexanes(50:50) to obtain Example 6 as a solid (5.0 g).

MS: m/z 521 (M+H)⁺

EXAMPLE 7

The compound of Example 6 is saponified to afford the carboxylic acid bythe general method employed in preparation of Intermediate 2A, to affordIntermediate 7A.

Intermediate 7A (0.050 g, 0.099 mM) in 3 mL of DCM is added 2 drops eachof BF₃.Et₂O and H₃PO₄. The solution is then transferred to −78° C. andisobutylene gas bubbled through for 3 min and then allowed to warm to rtand stirred for 12 h. The solution is extracted with saturated NaHCO₃(2×10 mL), dried over Na₂SO₄ and concentrated to an oil which ispurified on silica gel eluted with EtOAc/hexanes (30.70) to obtainExample 7 as a white solid (0.055 g).

MS: m/z 619 (M+H)⁺

EXAMPLE 8

To Example 6 (0.05 g, 0.096 mmol) in 1 mL of THF is added 6 uL ofisobutyl alcohol and triphenylphosphine (0.025 g, 0.096 mmol) followedby dropwise addition of diisopropyl azodicarboxylate (0.019 g, 0.096mmol) at 0° C. The reaction is allowed to warm to rt and stirred for 18h. The solvent is removed under reduced pressure and the oil obtainedpurified by flash chromatography on silica gel eluting with EtOAc/hexane(30:70) to yield Intermediate 8A as an oil (43.6 mg, 79%). Intermediate8A is hydrolyzed to with 1 M KOH solution in dioxane at 80° C. toprovide the acid Intermediate 8B (0.015 g).

Intermediate 8B (0.015 g, 0.026 mmol) is dissolved in 1 mL of DCM andHBTU (0.020 g, 0.054 mmol) added. The mixture is stirred for 1 h and 100uL of TEA is added followed by N,N-diethylethanolamine (0.021 g, 0.180mmol). The resulting solution is stirred for 18 h. After concentratingunder reduced pressure, the crude product is purified on silica geleluted with EtOAc/hexane (50/50) to provide Example 8 as a solid (0.014g).

LC: T_(r) 2.20 min; MS:m/z 662 (M+H)⁺

EXAMPLE 9

Example 8 (7 mg) is treated with 4N HCl/dioxane as described orIntermediate 1A. The product (5 mg) is isolated as for Example 1 toafford Example 9.

MS: m/z 552 (M+H)⁺

EXAMPLE 10

To a solution of BOC -D-phenylalanine (1.33 g) in DCM (15 mL), HOBT (743mg) and DCC (1.24 g) were added at rt. After 2 h TEA (1.2 mL) and4-diethylaminoethoxycarbonyl-2-butoxyaniline hydrochloride (1.73 g) wereadded followed by DMAP (60 mg). The reaction mixture is then stirred atrt for 3 d and filtered to remove dicyclohexylurea. The filtrate isconcentrated and purified on a silica gel column chromatography toafford 1.9 g of Example 10.

LC: T_(r) 2.05 min; MS: m/z 556 (M+H)⁺

EXAMPLE 11

Example 10 (47 mg) is stirred in 4M HCl in dioxane (2 mL) for 3 h.Product is isolated as for Example 1 to afford Example 11 as a paleyellow solid (38 mg).

C: T_(r) 0.83 min; MS: m/z 456 (M+H)⁺

EXAMPLE 12

Example 1 (80 mg) is dissolved in anhydrous acetonitrile (3 mL) andtreated with DIEA (60 μL) and N,N′-bis-BOC-1-guanylpyrazole (60 mg). Theresulting mixture is then refluxed overnight. The reaction mixture isthen cooled to rt and diluted with EtOAc (5 mL). The mixture is washedwith water and brine and dried over anhydrous sodium sulfate. Solvent isremoved in vacuo and the residue obtained is purified by silica gelcolumn chromatography to afford the BOC-protected guanadino productIntermediate 12A (12 mg).

NMR: (acetone-d6) 8.8 (br s, 1H), 8.20 (d, 1H), 7.2-7.8 (m, 9H), 4.95(dd, 1H), 4.2 (br s, 2H), 3.65-3.85 (m, 4H), 3.0-3.3 (m, 4H), 1.25 (s,9H), 1.20 (m, 4H), 1.15 (s, 9H), 0.95 (3, 3H)

MS: m/z 748 (M+H)⁺

Intermediate 12A (12 mg) is treated with 4M HCl/dioxane (0.5 mL) toremove the BOC group as described for Intermediate 1A, affording Example12 (4 mg).

MS: m/z 549 (M+H)⁺

EXAMPLE 13

53 mg (0.084 mmole) of Example 4 is dissolved in 5 mL methanol. To thisis added 10 μL of acetone. After 40 min, 0.10 mL of 1 M sodiumcyanoborohydride in THF is added. The reaction is stirred overnight, thesolvent removed in vacuo, and the crude compound purified by flashchromatography on silica gel (4:1 hexane: EtOAc, 10% TEA) to yield 22 mgof Example 14.

LC: T_(r) 1.77 min; MS: m/z 603 (M+H)⁺

EXAMPLE 14

106 mg (0.168 mmol) of Example 4 is dissolved in 5 mL methanol. To thisis added 60 μL of benzaldehyde, with stirring. After 12 h, 0.50 mL of 1M sodium cyanoborohydride in THF is added. The reaction is stirredovernight, the solvent removed in vacuo, and the crude compound purifiedby flash chromatography on silica gel (4:1 hexane: EtOAc, 10% TEA) toyield 48.3 mg of Example 14.

LC: T_(r) 1.83 min; MS: m/z 653 (M+H)⁺

EXAMPLE 15

12 mg (0.019 mmole) of Example 4 is suspended in 3.5 mL dry DCM. To thisis added 10 μL of methanesulfonyl chloride (0.13 mmole). The reaction isstirred overnight, then an additional 10 μL of methanesulfonyl chlorideis added and the reaction allowed to stir for an additional 24 h. Thesolvent is removed in vacuo to yield 12.2 mg of Example 15.

LC: T_(r) 1.99 min; MS: m/z 640 (M+H)⁺

EXAMPLE 16

15 mg (0.024 mmole) of Example 4 is suspended in 4.0 mL dry DCM. To thisis added 10 μL (0.078 mmole) of benzenesulfonyl chloride. The reactionis stirred overnight, then an additional 10 μL of benzenesulfonylchloride is added and the reaction allowed to stir for an additional 24h. The solvent is removed in vacuo to yield 16.8 mg of Example 16.

LC: T_(r) 2.05 min; MS: m/z 702 (M+H)⁺

EXAMPLE 17

25 mg (0.040 mmole) of Example 4 is suspended in 5 mL dry DCM. To thisis added 50 μL of ethyl isocyanate (0.63 mmole). The reaction is stirredovernight, and the solvent is removed in vacuo to yield 25.2 mg ofExample 17.

LC: T_(r) 1.99 min; MS: m/z 633 (M+H)⁺

EXAMPLE 18

20 mg (0.032 mmole) of Example 4 is suspended in 5 mL dry DCM. To thisis added 50 μL of tert-butyl isocyanate (0.44 mmole, 13.7 eq.). Thereaction is stirred overnight, then an additional 50 μL of tert-butylisocyanate is added and the reaction allowed to stir for an additional24 h. The solvent is removed in vacuo to yield 21.1 mg of Example 18.

LC: T_(r) 1.97 min; MS: m/z 661 (M+H)⁺

EXAMPLE 19

To a solution of BOC-D-Tyr(Bzl)-OH (279 mg) and 4-aminoresorcinolhydrochloride (135 mg) in acetonitrile (2 mL) at rt, HBTU (285 mg) andpyridine (145 μL) were added in succession. The resulting mixture isstirred overnight. The deep reddish reaction mixture is diluted withEtOAc/water (5 mL/3 mL) and the layers were separated. The aqueous layeris further extracted with EtOAC (5 mL). The organic layers were combinedand washed with water and brine and dried over Na₂SO₄. The solution isfiltered and the solvent is removed in vacuo. The resulting crudeproduct is purified by silica gel column chromatography usingmethanol/CHCl₃/hexane (1:20:20) as eluent to afford 300 mg of the amideIntermediate 19A.

LC:T_(r) 2.17 min; MS:m/z 479 (M+H)⁺

120 mg of Intermediate 19A is dissolved in THF (2 mL) at rt and addedwith triphenyl phosphine (197 mg), and N,N-diethylaminoethanol (100 μL).The resulting solution is cooled to 0° C. and treated with diisopropylazodicarboxylate (DIAD) (152 mg). The reaction is allowed to proceedovernight with gradual warming up to rt. The reaction mixture is dilutedwith EtOAc/water (5 mL/3 mL) and the layers were separated. The aqueouslayer is further extracted with EtOAc (5 mL). The organic layers werecombined and washed with water and brine and dried over Na₂SO₄. Thesolution is filtered and the solvent is removed in vacuo. The resultingcrude product is purified by silica gel column chromatography usingNEt₃/methanol/CHCl₃/hexane (1:2:40:40) as eluent to afford 100 mg ofExample 19.

LC: T_(r) 1.80 min; MS: m/z 677 (M+H)⁺

EXAMPLE 20

50 mg of Example 19 is stirred in 4M HCl in dioxane (1 mL) for 3 h.Product is isolated as for Example 1 to afford Example 21 as a paleyellow solid (35 mg).

MS: m/z 576 (M+H)⁺

EXAMPLE 21

120 mg of Example 19 is dissolved in THF (2 mL) at rt and added withtriphenyl phosphine (197 mg), and N,N-diethylaminopropanol (115 μL). Theresulting solution is cooled to 0° C. and added with diisopropylazodicarboxylate (DIAD) (152 mg). The reaction is allowed to proceedovernight with gradual warming up to rt. The reaction mixture is dilutedwith EtOAc/water (5 mL/3 mL) and the layers were separated. The aqueouslayer is further extracted with EtOAc (5 mL). The organic layers werecombined and washed with water and brine and dried over Na₂SO₄. Thesolution is filtered and the solvent is removed in vacuo. The resultingcrude product is purified by silica gel column chromatography usingtriethylamine/methanol/CHCl₃/hexane (1:2:40:40) as eluent to afford 50mg of Example 21.

LC: T_(r) 1.84 min; MS: m/z 705 (M+H)⁺

EXAMPLE 22

30 mg of Example 21 is stirred in 4M HCl in dioxane (1 mL) for 3 h.Product is isolated as for Example 1 to afford Example 22 as a paleyellow solid (20 mg).

MS: m/z 604 (M+H)⁺

EXAMPLE 23

To example 6 (0.05 g, 0.096 mmol) in 1 mL of THF is added 6 uL offurfuryl alcohol and triphenylphosphine (0.025 g, 0.096 mmol) followedby dropwise addition of diisopropyl azodicarboxylate (0.019 g, 0.096mmol) at 0° C. The reaction is allowed to warm to rt and stirred for 18h. The solvent is removed under reduced pressure and the oil obtainedpurified by flash chromatography on silica gel eluting with EtOAc/hexane(30:70) to yield the aryl ether Intermediate 23A as an oil (43.0 mg).Intermediate 23A is hydrolyzed to the carboxylic acid using 1 M KOHsolution in dioxane at 80° C. The acid obtained (0.02 g, 0.036 mmol) isdissolved in 1 mL of DCM and HBTU (0.015 g, 0.039 mmol) added. Themixture is stirred for 1 h and 36 uL of TEA is added followed byN,N-diethylethanolamine (0.015 g, 0.130 mmol). The resulting solution isstirred for 18 h. After concentrating under reduced pressure, the crudeproduct is purified on silica gel eluting with EtOAc/hexane (1:1) toobtain Example 23 as a solid (0.015 g).

MS: m/z 686 (M+H)⁺

EXAMPLE 24

Example 23 (7 mg) is treated with 4N HCl/dioxane as described forIntermediate 1A, and the product is isolated as for Example 1 to obtainExample 24 (4 mg).

LC: T_(r) 1.87 min; MS: m/z 586 (M+H)⁺

EXAMPLE 25

20 mg of Example 1 is dissolved in pyridine (100 μL) and treated withacetic anhydride (100 μL) at rt and stirred for 1 h. The reactionmixture is added with ice/water mixture and extracted with EtOAc. Theorganic layers were combined and washed with 5% aqueous CuSO₄, water andbrine and dried over Na₂SO₄. The solution is filtered and the solvent isremoved in vacuo to provide Example 25 as a pale white solid (15 mg).

LC: T_(r) 1.90 min; MS:m/z 548 (M+H)⁺

EXAMPLE 26

30 mg of Example 4 is dissolved in pyridine (200 μL) and treated withacetic anhydride (150 μL) at rt and stirred for 1 h. The reactionmixture is treated with ice/water mixture and extracted with EtOAC. Theorganic layers were combined and washed with 5% aqueous CuSO₄, water andbrine and dried over Na₂SO₄. The solvent is removed in vacuo to provideExample 26 as a pale white solid (25 mg).

LC: T_(r) 1.97 min; MS: m/z 604 (M+H)⁺

In the above schemes, “PG” represents an amino protecting group. Theterm “amino protecting group” as used herein refers to substituents ofthe amino group commonly employed to block or protect the aminofunctionality while reacting other functional groups on the compound.Examples of such amino-protecting groups include the formyl group, thetrityl group, the phthalimido group, the trichloroacetyl group, thechloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blockinggroups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1methylcyclopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,9-fluorenylmethoxycarbonyl (“FMOC”), t-butoxycarbonyl (“BOC”),2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; thebenzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, thediphenylphosphine oxide group and like amino-protecting groups. Thespecies of amino-protecting group employed is not critical so long asthe derivatized amino group is stable to the condition of subsequentreaction(s) on other positions of the compound of Formula (I) and can beremoved at the desired point without disrupting the remainder of themolecule. Preferred amino-protecting groups are the allyloxycarbonyl,the t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the trityl groups.Similar amino-protecting groups used in the cephalosporin, penicillinand peptide art are also embraced by the above terms. Further examplesof groups referred to by the above terms are described by J. W. Barton,“Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., PlenumPress, New York, N.Y., 1973, Chapter 2, and T. W. Greene, “ProtectiveGroups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981,Chapter 7. The related term “protected amino” defines an amino groupsubstituted with an amino-protecting group discussed above.

In Scheme 1, other methods of coupling or acylating the protected aminoacid to the compound of formula R⁴NH₂ can be utilized, for exampleDCC/HBT, HBTU, and BOP and other methods, including but not limited tothose listed in: Fernando Albericio and Louis A. Carpino “CouplingReagents and Activation” in Methods in Enzymology vol. 289 (Gregg B.Fields ed), pp 104-126, Academic Press, San Diego, 1997.

I. Biological Assay

The following assay method is utilized to identify compounds of Formula(I) which are effective in binding with RAGE, and hence useful asmodulators, preferably antagonists of RAGE. This method is alsodescribed in U.S. Pat. No. 6,908,741.

General Assay Procedure

S100b, β-amyloid and CML (500 ng/100 μL/well) in 100 mM sodiumbicarbonate/sodium carbonate buffer (pH 9.8) is loaded onto the wells ofa NUNC Maxisorp flat bottom 96—well microtitre plate. The plate isincubated at 4° C. overnight. The wells are aspirated and treated with50 mM imidazole buffer saline (pH 7.2) (with 1 mM CaCl₂/MgCl₂)containing 1% bovine serum albumin (BSA) (300 μL/well) for two h at 37°C. The wells are aspirated and washed 3 times (400 μL/well) with 155 mMNaCl pH 7.2 buffer saline and soaked 10 seconds between each wash.

Test compounds are dissolved in nanopure water (concentration: 10-100μM). DMSO may be used as co-solvent. 25 μL of test compound solution in2% DMSO is added, along with 75 μL sRAGE (4.0×10⁻⁴ mg/mL FAC) to eachwell and samples are incubated for 1 h at 37° C. The wells are washed 3times with 155 mM NaCl pH 7.2 buffer saline and are soaked 10 secondsbetween each wash. Non-radioactive binding is performed by adding:

10 μL Biotinylated goat F(ab′)2 Anti-mouse IgG. (8.0×10⁻⁴ mg/mL, FAC)

10 μL Alk-phos-Sterptavidin (3×10⁻³ mg/mL FAC)

10 μL Polyclonal antibody for sRAGE (FAC 6.0×10⁻³ mg/mL) to 5 mL 50 mMimidazole buffer saline (pH 7.2) containing 0.2% bovine serum albuminand 1 mM CaCl₂. The mixture is incubated for 30 minutes at 37° C. 100 μLcomplex is added to each well and incubation is allowed to proceed at rtfor 1 h. Wells are washed 3 times with wash buffer and soaked 10 sbetween each wash. 100 μL 1 mg/mL (pNPP) in 1 M diethanolamine (pHadjusted to 9.8 with HCl) is added. Color is allowed to develop in thedark for 1 to 2 h at rt. The reaction is quenched with 10 μL of stopsolution (0.5 N NaOH in 50% ethanol) and the absorbance is measuredspectrophotometrically with a microplate reader at 405 nm.

The following compounds of Formula 1 were synthesized according to theSchemes and tested according to the assay method described above.

IC₅₀ (μM) of ELISA assay represents the concentration of compound atwhich 50% signal has been inhibited.

Compound inhibition of S-100b/RAGE interaction in Glioma cells byExample 1 had an IC50 of 3.3 μM. Thus, the cell based assay demonstratedeffective correlation with the binding of ELISA IC₅₀ value (1.75 μM).Functional Assay IC₅₀ (μM) Example Inhibition of ELISA No. NF-κB inGlioma Cells Assay (S-100b) 1 3.3 1.75

ELISA Assay IC₅₀ (μM) Carboxymethyl Example No. S-100b Amyloid-β Lysine(CML) 1 1.75 3.4 2.29 2 5.1 — 3.16 3 1.32 1.5 1.5 4 0.82 2.2 1.12 5 2.881.81 1.27 6 6.3 NA NA 7 1-3 — 8 8 2.0 NA NA 9 1.6 NA NA 10 0.95 NA NA 1110-30 NA NA 12 0.3-1.0 5 0.7 13 1 1 0.7 14 2.8 NA NA 15 10-30 NA NA 1620-30 NA NA 17 10 NA NA 18 2.3 2 0.84 19 1.14 0.80 0.80 20 0.84 1 1 210.64 1.23 0.46 22 0.92 1.73 0.68 23 15.5 NA NA 24 2.7 NA NA 25 15 NA NA26 5.6 NA NANA = ELISA assay data not available

The invention further provides pharmaceutical compositions comprisingthe RAGE modulating compounds of the invention. The term “pharmaceuticalcomposition” is used herein to denote a composition that may beadministered to a mammalian host, e.g., orally, topically, parenterally,by inhalation spray, or rectally, in unit dosage formulations containingconventional non-toxic carriers, diluents, adjuvants, vehicles and thelike. The term “parenteral” as used herein, includes subcutaneousinjections, intravenous, intramuscular, intracisternal injection, or byinfusion techniques.

The pharmaceutical compositions containing a compound of the inventionmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous, or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anyknown method, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxicpharmaceutically-acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,356,108;4,166,452; and 4,265,874, incorporated herein by reference, to formosmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or a softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may contain the active compounds in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyl-eneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as a liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alchol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring, and coloringagents may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oil, or a mineral oil, for example aliquid paraffin, or a mixture thereof. Suitable emulsifying agents maybe naturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectible aqueous or oleaginous suspension. This suspension may beformulated according to the known methods using suitable dispersing orwetting agents and suspending agents described above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conveniently employed as solvent or suspending medium. For thispurpose, any bland fixed oil may be employed using synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compositions may also be in the form of suppositories for rectaladministration of the compounds of the invention. These compositions canbe prepared by mixing the drug with a suitable non-irritating excipientwhich is solid at ordinary temperatures but liquid at the rectaltemperature and will thus melt in the rectum to release the drug. Suchmaterials include cocoa butter and polyethylene glycols, for example.

For topical use, creams, ointments, jellies, solutions of suspensions,etc., containing the compounds of the invention are contemplated. Forthe purpose of this application, topical applications shall includemouth washes and gargles. The compounds of the present invention mayalso be administered in the form of liposome delivery systems, such assmall unilamellar vesicles, large unilamellar vesicles, andmultilamellar vesicles. Liposomes may be formed from a variety ofphospholipids, such as cholesterol, stearylamine, orphosphatidylcholines. Also provided by the present invention areprodrugs of the invention.

Pharmaceutically-acceptable salts of the compounds of the presentinvention, where a basic or acidic group is present in the structure,are also included within the scope of the invention. The term“pharmaceutically acceptable salts” refers to non-toxic salts of thecompounds of this invention which are generally prepared by reacting thefree base with a suitable organic or inorganic acid or by reacting theacid with a suitable organic or inorganic base. Representative saltsinclude the following salts: Acetate, Benzenesulfonate, Benzoate,Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate,Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride,Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate,Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine,Hydrobromide, Hydrocloride. Hydroxynaphthoate, Iodide, Isethionate,Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate,Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate(Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate,Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide,Trimethylammonium and Valerate. When an acidic substituent is present,such as —COOH, there can be formed the ammonium, morpholinium, sodium,potassium, barium, calcium salt, and the like, for use as the dosageform. When a basic group is present, such as amino or a basic heteroarylradical, such as pyridyl, an acidic salt, such as hydrochloride,hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate,acetate, oxiate, maleate, pyruvate, malonate, succinate, citrate,tartarate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate,ethanesulfonate, picrate and the like, and include acids related to thepharmaceutically-acceptable salts listed in the Journal ofPharmaceutical Science, 66, 2 (1977) p. 1-19.

Other salts which are not pharmaceutically acceptable may be useful inthe preparation of compounds of the invention and these form a furtheraspect of the invention.

In addition, some of the compounds of the present invention may formsolvates with water or common organic solvents. Such solvates are alsoencompassed within the scope of the invention.

Thus, in a further embodiment, there is provided a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt, solvate, or prodrug therof, and one ormore pharmaceutically acceptable carriers, excipients, or diluents.

The compounds of the present invention selectively act as modulators ofRAGE binding to a single endogenous ligand, i.e., selective modulatorsof β-amyloid—RAGE interaction, and therefore are especially advantageousin treatment of Alzheimer's disease and related dementias.

Further, the compounds of the present invention act as modulators ofRAGE interaction with two or more endogenous ligands in preference toothers. Such compounds are advantageous in treatment of related orunrelated pathologies mediated by RAGE, i.e., Alzheimer's disease andcancer.

Further, the compounds of the present invention act as modulators ofRAGE binding to each and every one of its ligands, thereby preventingthe generation of oxidative stress and activation of NF-κB regulatedgenes, such as the cytokines IL-1, and TNF-α. Thus, antagonizing thebinding of physiological ligands to RAGE prevent targetedpathophysiological consequences and useful for management or treatmentof diseases, i.e., AGE-RAGE interaction leading to diabeticcomplications, S100/EN-RAGE/calgranulin-RAGE interaction leading toinflammatory diseases, β-amyloid-RAGE interaction leading to Alzheimer'sDisease, and amphoterin-RAGE interaction leading to cancer.

I. RAGE and the Complications of Diabetes

As noted above, the compounds of the present invention are useful in thetreatment of the complications of diabetes. It has been shown thatnonenzymatic glycoxidation of macromolecules ultimately resulting in theformation of advanced glycation endproducts (AGEs) is enhanced at sitesof inflammation, in renal failure, in the presence of hyperglycemia andother conditions associated with systemic or local oxidant stress (Dyer,D., et al., J. Clin. Invest., 91:2463-2469 (1993); Reddy, S., et al.,Biochem., 34:10872-10878 (1995); Dyer, D., et al., J. Biol. Chem.,266:11654-11660 (1991); Degenhardt, T., et al., Cell Mol. Biol.,44:1139-1145 (1998)). Accumulation of AGEs in the vasculature can occurfocally, as in the joint amyloid composed of AGE-β₂-microglobulin foundin patients with dialysis-related amyloidosis (Miyata, T., et al., J.Clin. Invest., 92:1243-1252 (1993); Miyata, T., et al., J. Clin.Invest., 98:1088-1094 (1996)), or generally, as exemplified by thevasculature and tissues of patients with diabetes (Schmidt, A-M., etal., Nature Med., 1: 1002-1004 (1995)). The progressive accumulation ofAGEs over time in patients with diabetes suggests that endogenousclearance mechanisms are not able to function effectively at sites ofAGE deposition. Such accumulated AGEs have the capacity to altercellular properties by a number of mechanisms. Although RAGE isexpressed at low levels in normal tissues and vasculature, in anenvironment where the receptor's ligands accumulate, it has been shownthat RAGE becomes upregulated (Li, J. et al., J. Biol. Chem.,272:16498-16506 (1997); Li, J., et al., J. Biol. Chem., 273:30870-30878(1998); Tanaka, N., et al., J. Biol. Chem,. 275:25781-25790(2000)). RAGEexpression is increased in endothelium, smooth muscle cells andinfiltrating mononuclear phagocytes in diabetic vasculature. Also,studies in cell culture have demonstrated that AGE-RAGE interactioncaused changes in cellular properties important in vascular homeostasis.

II. RAGE and Cellular Dysfunction in the Amyloidoses

Also as noted above, the compounds of the present invention are usefulin treating amyloidoses and Alzheimer's disease. RAGE appears to be acell surface receptor which binds β-sheet fibrillar material regardlessof the composition of the subunits (amyloid-β peptide, Aβ, amylin, serumamyloid A, prion-derived peptide) (Yan, S.-D., et al., Nature,382:685-691 (1996); Yan, S-D., et al., Nat. Med., 6:643-651 (2000)).Deposition of amyloid has been shown to result in enhanced expression ofRAGE. For example, in the brains of patients with Alzheimer's disease(AD), RAGE expression increases in neurons and glia (Yan, S.-D., et al.,Nature 382:685-691 (1996)). The consequences of AB interaction with RAGEappear to be quite different on neurons versus microglia. Whereasmicroglia become activated as a consequence of Aβ-RAGE interaction, asreflected by increased motility and expression of cytokines, earlyRAGE-mediated neuronal activation is superceded by cytotoxicity at latertimes. Further evidence of a role for RAGE in cellular interactions ofAβ concerns inhibition of Aβ-induced cerebral vasoconstriction andtransfer of the peptide across the blood-brain barrier to brainparenchyma when the receptor was blocked (Kumar, S., et al., Neurosci.Program, p141-#275.19 (2000)). Inhibition of RAGE-amyloid interactionhas been shown to decrease expression of cellular RAGE and cell stressmarkers (as well as NF-kB activation), and diminish amyloid deposition(Yan, S-D., et al., Nat. Med., 6:643-651 (2000)) suggesting a role forRAGE-amyloid interaction in both perturbation of cellular properties inan environment enriched for amyloid (even at early stages) as well as inamyloid accumulation.

III. RAGE and Propagation of the Immune/Inflammatory Response

As noted above, the compounds of the present invention are useful intreating inflammation. For example, S100/calgranulins have been shown tocomprise a family of closely related calcium-binding polypeptidescharacterized by two EF-hand regions linked by a connecting peptide(Schafer, B. et al., TIBS, 21:134-140 (1996); Zimmer, D., et al., BrainRes. Bull., 37:417-429 (1995); Rammes, A., et al., J. Biol. Chem.,272:9496-9502 (1997); Lugering, N., et al., Eur. J. Clin. Invest.,25:659-664 (1995)). Although they lack signal peptides, it has long beenknown that S100/calgranulins gain access to the extracellular space,especially at sites of chronic immune/inflammatory responses, as incystic fibrosis and rheumatoid arthritis. RAGE is a receptor for manymembers of the S100/calgranulin family, mediating their proinflammatoryeffects on cells such as lymphocytes and mononuclear phagocytes. Also,studies on delayed-type hypersensitivity response, colitis in IL-10 nullmice, collagen-induced arthritis, and experimental autoimmuneencephalitis models suggest that RAGE-ligand interaction (presumablywith S100/calgranulins) has a proximal role in the inflammatory cascade.

IV. RAGE and Amphoterin

As noted above, the compounds of the present invention are useful intreating tumor and tumor metastasis. For example, amphoterin is a highmobility group I nonhistone chromosomal DNA binding protein (Rauvala,H., et al., J. Biol. Chem., 262:16625-16635 (1987); Parkikinen, J., etal., J. Biol. Chem. 268:19726-19738 (1993)) which has been shown tointeract with RAGE. It has been shown that amphoterin promotes neuriteoutgrowth, as well as serving as a surface for assembly of proteasecomplexes in the fibrinolytic system (also known to contribute to cellmobility). In addition, a local tumor growth inhibitory effect ofblocking RAGE has been observed in a primary tumor model (C6 glioma),the Lewis lung metastasis model (Taguchi, A., et al., Nature 405:354-360(2000)), and spontaneously arising papillomas in mice expressing thev-Ha-ras transgene (Leder, A., et al., Proc. Natl. Acad. Sci.,87:9178-9182 (1990)).

Amphoterin is a high mobility group I nonhistone chromosomal DNA bindingprotein (Rauvala, H. and R. Pihlaskari. 1987. Isolation and somecharacteristics of an adhesive factor of brain that enhances neuriteoutgrowth in central neurons. J. Biol. Chem. 262:16625-16635.(Parkikinen, J., E. Raulo, J. Merenmies, R. Nolo, E. Kajander, M.Baumann, and H. Rauvala. 1993. Amphoterin, the 30 kDa protein in afamily of HIMG1-type polypeptides. J. Biol. Chem. 268:19 726-19738).

V. RAGE and Erectile Dysfunction

Relaxation of the smooth muscle cells in the cavernosal arterioles andsinuses results in increased blood flow into the penis, raising corpuscavernosum pressure to culminate in penile erection. Nitric oxide isconsidered the principle stimulator of cavernosal smooth musclerelaxation (See Wingard C J, Clinton W, Branam H, Stopper V S, Lewis RW, Mills T M, Chitaley K. Antagonism of Rho-kinase stimulates rat penileerection via a nitric oxide-independent pathway. Nature Medicine 2001January; 7(1):119-122). RAGE activation produces oxidants (See Yan,S-D., Schmidt A-M., Anderson, G., Zhang, J., Brett, J., Zou, Y-S.,Pinsky, D., and Stern, D. Enhanced cellular oxidant stress by theinteraction of advanced glycation endproducts with theirreceptors/binding proteins. J. Biol. Chem. 269:9889-9887, 1994.) via anNADH oxidase-like enzyme, therefore suppressing the circulation ofnitric oxide. Potentially by inhibiting the activation of RAGE signalingpathways by decreasing the intracellular production of AGEs, generationof oxidants will be attenuated. RAGE blockers may promote and facilitatepenile erection by blocking the access of ligands to RAGE.

The calcium-sensitizing Rho-kinase pathway may play a synergistic rolein cavernosal vasoconstriction to maintain penile flaccidity. Theantagonism of Rho-kinase results in increased corpus cavernosumpressure, initiating the erectile response independently of nitric oxide(Wingard et al.). One of the signaling mechanisms activated by RAGEinvolves the Rho-kinase family such as cdc42 and rac (See Huttunen H J,Fages C, Rauvala H. Receptor for advanced glycation end products(RAGE)-mediated neurite outgrowth and activation of NF-kappaB requirethe cytoplasmic domain of the receptor but different downstreamsignaling pathways. J Biol Chem 1999 Jul. 9;274(28):19919-24). Thus,inhibiting activation of Rho-kinases via suppression of RAGE signalingpathways will enhance and stimulate penile erection independently ofnitric oxide.

Thus, in a further aspect, the present invention provides a method forthe inhibition of the interaction of RAGE with physiological ligands. Ina preferred embodiment of this aspect, the present invention provides amethod for treating a disease state selected from the group consistingof acute and chronic inflammation, symptoms of diabetes, vascularpermeability, nephropathy, atherosclerosis, retinopathy, Alzheimer'sdisease, erectile dysfunction, and tumor invasion and/or metastasis,which comprises administering to a subject in need thereof a compound ofthe present invention, preferably a pharmacologically effective amount,more preferably a therapeutically effective amount. In a preferredembodiment, at least one compound of Formula (I) is utilized, eitheralone or in combination with one or more known therapeutic agents. In afurther preferred embodiment, the present invention provides method ofprevention and/or treatment of RAGE mediated human diseases, treatmentcomprising alleviation of one or more symptoms resulting from thatdisorder, to an outright cure for that particular disorder or preventionof the onset of the disorder, the method comprising administration to ahuman in need thereof a therapeutically effective amount of a compoundof the present invention, preferably a compound of Formula (I).

In this method, factors which will influence what constitutes aneffective amount will depend upon the size and weight of the subject,the biodegradability of the therapeutic agent, the activity of thetherapeutic agent, as well as its bioavailability. As used herein, thephrase “a subject in need thereof” includes mammalian subjects,preferably humans, who either suffer from one or more of the aforesaiddiseases or disease states or are at risk for such. Accordingly, in thecontext of the therapeutic method of the invention, this method also iscomprised of a method for treating a mammalian subject prophylactically,or prior to the onset of diagnosis such disease(s) or disease state(s).

In a further aspect of the present invention, the RAGE modulators of theinvention are utilized in adjuvant therapeutic or combinationtherapeutic treatments with other known therapeutic agents.

The term “treatment” as used herein, refers to the full spectrum oftreatments for a given disorder from which the patient is suffering,including alleviation of one, most of all symptoms resulting from thatdisorder, to an outright cure for the particular disorder or preventionof the onset of the disorder.

The following is a non-exhaustive listing of adjuvants and additionaltherapeutic agents which may be utilized in combination with the RAGEmodulators of the present invention:

Pharmacologic classifications of anticancer agents:

-   1. Alkylating agents: Cyclophosphamide, nitrosoureas, carboplatin,    cisplatin, procarbazine-   2. Antibiotics: Bleomycin, Daunorubicin, Doxorubicin-   3. Antimetabolites: Methotrexate, Cytarabine, Fluorouracil-   4. Plant alkaloids: Vinblastine, Vincristine, Etoposide, Paclitaxel,-   5. Hormones: Tamoxifen, Octreotide acetate, Finasteride, Flutamide-   6. Biologic response modifiers: Interferons, Interleukins,

Pharmacologic classifications of treatment for Rheumatoid Arthritis(Inflammation)

-   1. Analgesics: Aspirin-   2. NSAIDs (Nonsteroidal anti-inflammatory drugs): Ibuprofen,    Naproxen, Diclofenac-   3. DMARDs (Disease-Modifying Antirheumatic drugs): Methotrexate,    gold preparations, hydroxychloroquine, sulfasalazine-   4. Biologic Response Modifiers, DMARDs: Etanercept, Infliximab    Glucocorticoids

Pharmacologic classifications of treatment for Diabetes Mellitus

-   1. Sulfonylureas: Tolbutamide, Tolazamide, Glyburide, Glipizide-   2. Biguanides: Metformin-   3. Miscellaneous oral agents: Acarbose, Troglitazone-   4. Insulin

Pharmacologic classifications of treatment for Alzheimer's Disease

-   1. Cholinesterase Inhibitor: Tacrine, Donepezil-   2. Antipsychotics: Haloperidol, Thioridazine-   3. Antidepressants: Desipramine, Fluoxetine, Trazodone, Paroxetine-   4. Anticonvulsants: Carbamazepine, Valproic acid

In a further preferred embodiment, the present invention provides amethod of treating RAGE mediated diseases, the method comprisingadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of Formula (I) in combination with therapeuticagents selected from the group consisting of alkylating agents,antimetabolites, plant alkaloids, antibiotics, hormones, biologicresponse modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids,sulfonylureas, biguanides, insulin, cholinesterase inhibitors,antipsychotics, antidepressants, and anticonvulsants. In a furtherpreferred embodiment, the present invention provides the pharmaceuticalcomposition of the invention as described above, further comprising oneor more therapeutic agents selected from the group consisting ofalkylating agents, antimetabolites, plant alkaloids, antibiotics,hormones, biologic response modifiers, analgesics, NSAIDs, DMARDs,glucocorticoids, sulfonylureas, biguanides, insulin, cholinesteraseinhibitors, antipsychotics, antidepressants, and anticonvulsants.

Generally speaking, the compound of the present invention, preferablyFormula (I), is administered at a dosage level of from about 0.01 to 500mg/kg of the body weight of the subject being treated, with a preferreddosage range between 0.01 and 200 mg/kg, most preferably 0.1 to 100mg/kg of body weight per day. The amount of active ingredient that maybe combined with the carrier materials to produce a single dosage willvary depending upon the host treated and the particular mode ofadministration. For example, a formulation intended for oraladministration to humans may contain 1 mg to 2 grams of a compound ofFormula (I) with an appropriate and convenient amount of carriermaterial which may vary from about 5 to 95 percent of the totalcomposition. Dosage unit forms will generally contain between from about5 mg to about 500 mg of active ingredient. This dosage has to beindividualized by the clinician based on the specific clinical conditionof the subject being treated. Thus, it will be understood that thespecific dosage level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, rate of excretion, drugcombination and the severity of the particular disease undergoingtherapy.

While the invention has been described and illustrated with reference tocertain preferred embodiments therof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferreddosages as set forth herein may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forRAGE-mediated disease(s). Likewise, the specific pharmacologicalresponses observed may vary according to and depending on the particularactive compound selected or whether there are present pharmaceuticalcarriers, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvention.

1. A method for the inhibition of the interaction of RAGE with itsphysiological ligands, which comprises administering to a subject inneed thereof, at least one compound comprising at least one moiety ofthe formula

wherein L₁ is a C₁-C₄ alkyl group and L₂ is a direct bond, and Aryl₁ andAryl₂ are aryl, wherein each of Aryl₁ and Aryl₂ are substituted by atleast one lipophilic group selected from the group consisting of a)—Y—C₁₋₆ alkyl; b) —Y-aryl; c) —Y—C-₁₋₆ alkylaryl; d)—Y—C₁₋₆-alkyl-NR₇R₈; e) —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; wherein R₁₈ andR₁₉ are independently selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ isselected from the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; R₇, R₈, R₉ and R₁₀ are independently selected from the groupconsisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; andwherein R₇ and R₈ may be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇and R₈ are attached, wherein m and n are, independently, 1, 2, 3, or 4;X is selected from the group consisting of —CH₂—, —O—, —S—, —S(O₂)—,—C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—O—C(O)—, —NHSO₂NH—,

a pharmaceutically acceptable salt thereof, wherein at least one ofAryl₁ and Aryl₂ is substituted with a lipophilic group of the formula—Y—C₁₋₆-alkyl-NR₇R₈.
 2. The method of claim 1, wherein the ligand(s)is(are) selected from advanced glycated end products (AGEs),S100/calgranulin/EN-RAGE, β-amyloid and amphoterin.
 3. The method ofclaim 1, wherein at least on of Aryl₁ or Aryl₂ is further substitutedwith a lipophilic group selected from the group consisting of C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylaryl, and C₁-C₆ alkoxyaryl.
 4. A methodfor treating acute and/or chronic inflammation, which comprisesadministering to a subject in need thereof a therapeutically effectiveamount of at least one compound comprising at least one moiety of theformula

wherein L₁ is a C₁-C₄ alkyl group and L₂ is a direct bond, and Aryl₁ andAryl₂ are aryl, wherein each of Aryl₁ and Aryl₂ are substituted by atleast one lipophilic group selected from the group consisting of a)—Y—C₁₋₆ alkyl; b) —Y-aryl; c) —Y—C-₁₋₆ alkylaryl; d)—Y—C₁₋₆-alkyl-NR₇R₈; e) —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; wherein R₁₈ andR₁₉ are independently selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ isselected from the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; R₇, R₈, R₉ and R₁₀ are independently selected from the groupconsisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; andwherein R₇ and R₈ may be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇and R₈ are attached, wherein m and n are, independently, 1, 2, 3, or 4;X is selected from the group consisting of —CH₂—, —O—, —S—, —S(O₂)—,—C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—O—C(O)—, —NHSO₂NH—,

a pharmaceutically acceptable salt thereof, wherein at least one ofAryl₁ and Aryl₂ is substituted with a lipophilic group of the formula—Y—C₁₋₆-alkyl-NR₇R₈.
 5. A method for treating vascular permeability,which comprises administering to a subject in need thereof atherapeutically effective amount of at least one compound comprising atleast one moiety of the formula

wherein L₁ is a C₁-C₄ alkyl group and L₂ is a direct bond, and Aryl₁ andAryl₂ are aryl, wherein each of Aryl₁ and Aryl₂ are substituted by atleast one lipophilic group selected from the group consisting of a)—Y—C₁₋₆ alkyl; b) —Y-aryl; c) —Y—C-₁₋₆ alkylaryl; d)—Y—C₁₋₆-alkyl-NR₇R₈; e) —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; wherein R₁₈ andR₁₉ are independently selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ isselected from the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; R₇, R₈, R₉ and R₁₀ are independently selected from the groupconsisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; andwherein R₇ and R₈ may be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇and R₈ are attached, wherein m and n are, independently, 1, 2, 3, or 4;X is selected from the group consisting of —CH₂—, —O—, —S—, —S(O₂)—,—C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—O—C(O)—, —NHSO₂NH—,

a pharmaceutically acceptable salt thereof, wherein at least one ofAryl₁ and Aryl₂ is substituted with a lipophilic group of the formula—Y—C₁₋₆-alkyl-NR₇R₈.
 6. A method for treating nephropathy, whichcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a compound of at least one compound comprising atleast one moiety of the formula

wherein L₁ is a C₁-C₄ alkyl group and L₂ is a direct bond, and Aryl₁ andAryl₂ are aryl, wherein each of Aryl₁ and Aryl₂ are substituted by atleast one lipophilic group selected from the group consisting of a)—Y—C₁₋₆ alkyl; b) —Y-aryl; c) —Y—C-₁₋₆ alkylaryl; d)—Y—C₁₋₆-alkyl-NR₇R₈; e) —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; wherein R₁₈ andR₁₉ are independently selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ isselected from the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; R₇, R₈, R₉ and R₁₀ are independently selected from the groupconsisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; andwherein R₇ and R₈ may be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇and R₈ are attached, wherein m and n are, independently, 1, 2, 3, or 4;X is selected from the group consisting of —CH₂—, —O—, —S—, —S(O₂)—,—C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—O—C(O)—, —NHSO₂NH—,

a pharmaceutically acceptable salt thereof, wherein at least one ofAryl₁ and Aryl₂ is substituted with a lipophilic group of the formula—Y—C₁₋₆-alkyl-NR₇R₈.
 7. A method for treating atherosclerosis, whichcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a compound of at least one compound comprising atleast one moiety of the formula

wherein L₁ is a C₁-C₄ alkyl group and L₂ is a direct bond, and Aryl₁ andAryl₂ are aryl, wherein each of Aryl₁ and Aryl₂ are substituted by atleast one lipophilic group selected from the group consisting of a)—Y—C₁₋₆ alkyl; b) —Y-aryl; c) —Y—C-₁₋₆ alkylaryl; d)—Y—C₁₋₆-alkyl-NR₇R₈; e) —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; wherein R₁₈ andR₁₉ are independently selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ isselected from the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; R₇, R₈, R₉ and R₁₀ are independently selected from the groupconsisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; andwherein R₇ and R₈ may be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇and R₈ are attached, wherein m and n are, independently, 1, 2, 3, or 4;X is selected from the group consisting of —CH₂—, —O—, —S—, —S(O₂)—,—C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—O—C(O)—, —NHSO₂NH—,

a pharmaceutically acceptable salt thereof, wherein at least one ofAryl₁ and Aryl₂ is substituted with a lipophilic group of the formula—Y—C₁₋₆-alkyl-NR₇R₈.
 8. A method for treating retinopathy, whichcomprises administering to a subject in need thereof a therapeuticallyeffective amount of compound of at least one compound comprising atleast one moiety of the formula

wherein L₁ is a C₁-C₄ alkyl group and L₂ is a direct bond, and Aryl₁ andAryl₂ are aryl, wherein each of Aryl₁ and Aryl₂ are substituted by atleast one lipophilic group selected from the group consisting of a)—Y—C₁₋₆ alkyl; b) —Y-aryl; c) —Y—C-₁₋₆ alkylaryl; d)—Y—C₁₋₆-alkyl-NR₇R₈; e) —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; wherein R₁₈ andR₁₉ are independently selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ isselected from the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; R₇, R₈, R₉ and R₁₀ are independently selected from the groupconsisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; andwherein R₇ and R₈ may be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇and R₈ are attached, wherein m and n are, independently, 1, 2, 3, or 4;X is selected from the group consisting of —CH₂—, —O—, —S—, —S(O₂)—,—C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—O—C(O)—, —NHSO₂NH—,

a pharmaceutically acceptable salt thereof, wherein at least one ofAryl₁ and Aryl₂ is substituted with a lipophilic group of the formula—Y—C₁₋₆-alkyl-NR₇R₈.
 9. A method for treating Alzheimer's disease, whichcomprises administering to a subject in need thereof a therapeuticallyeffective amount of at least one compound comprising at least one moietyof the formula

wherein L₁ is a C₁-C₄ alkyl group and L₂ is a direct bond, and Aryl₁ andAryl₂ are aryl, wherein each of Aryl₁ and Aryl₂ are substituted by atleast one lipophilic group selected from the group consisting of a)—Y—C₁₋₆ alkyl; b) —Y-aryl; c) —Y—C-₁₋₆ alkylaryl; d)—Y—C₁₋₆-alkyl-NR₇R₈; e) —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; wherein R₁₈ andR₁₉ are independently selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ isselected from the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; R₇, R₈, R₉ and R₁₀ are independently selected from the groupconsisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; andwherein R₇ and R₈ may be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇and R₈ are attached, wherein m and n are, independently, 1, 2, 3, or 4;X is selected from the group consisting of —CH₂—, —O—, —S—, —S(O₂)—,—C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—O—C(O)—, —NHSO₂NH—,

a pharmaceutically acceptable salt thereof, wherein at least one ofAryl₁ and Aryl₂ is substituted with a lipophilic group of the formula—Y—C₁₋₆-alkyl-NR₇R₈.
 10. A method for treating erectile dysfunction,which comprises administering to a subject in need thereof atherapeutically effective amount of a compound of at least one compoundcomprising at least one moiety of the formula

wherein L₁ is a C₁-C₄ alkyl group and L₂ is a direct bond, and Aryl₁ andAryl₂ are aryl, wherein each of Aryl₁ and Aryl₂ are substituted by atleast one lipophilic group selected from the group consisting of a)—Y—C₁₋₆ alkyl; b) —Y-aryl; c) —Y—C-₁₋₆ alkylaryl; d)—Y—C₁₋₆-alkyl-NR₇R₈; e) —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; wherein R₁₈ andR₁₉ are independently selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ isselected from the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; R₇, R₈, R₉ and R₁₀ are independently selected from the groupconsisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; andwherein R₇ and R₈ may be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇and R₈ are attached, wherein m and n are, independently, 1, 2, 3, or 4;X is selected from the group consisting of —CH₂—, —O—, —S—, —S(O₂)—,—C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—O—C(O)—, —NHSO₂NH—,

a pharmaceutically acceptable salt thereof, wherein at least one ofAryl₁ and Aryl₂ is substituted with a lipophilic group of the formula—Y—C₁₋₆-alkyl-NR₇R₈.
 11. A method for treating tumor invasion and/ormetastasis, which comprises administering to a subject in need thereof atherapeutically effective amount of at least one compound comprising atleast one moiety of the formula

wherein L₁ is a C₁-C₄ alkyl group and L₂ is a direct bond, and Aryl₁ andAryl₂ are aryl, wherein each of Aryl₁ and Aryl₂ are substituted by atleast one lipophilic group selected from the group consisting of a)—Y—C₁₋₆ alkyl; b) —Y-aryl; c) —Y—C-₁₋₆ alkylaryl; d)—Y—C₁₋₆-alkyl-NR₇R₈; e) —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; wherein R₁₈ andR₁₉ are independently selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ isselected from the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; R₇, R₉, R₉ and R₁₀ are independently selected from the groupconsisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; andwherein R₇ and R₈ may be taken together to form a ring having theformula —(CH₂)_(m)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇and R₈ are attached, wherein m and n are, independently, 1, 2, 3, or 4;X is selected from the group consisting of —CH₂—, —O—, —S—, —S(O₂)—,—C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—O—C(O)—, —NHSO₂NH—,

a pharmaceutically acceptable salt thereof, wherein at least one ofAryl₁ and Aryl₂ is substituted with a lipophilic group of the formula—Y—C₁₋₆-alkyl-NR₇R₈.
 12. A method of treating RAGE mediated diseases,the method comprising administering to a subject in need thereof, atherapeutically effective amount of at least one compound comprising atleast one moiety of the formula

wherein L₁ is a C₁-C₄ alkyl group and L₂ is a direct bond, and Aryl₁ andAryl₂ are aryl, wherein each of Aryl₁ and Aryl₂ are substituted by atleast one lipophilic group selected from the group consisting of a)—Y—C₁₋₆ alkyl; b) —Y-aryl; c) —Y—C-₁₋₆ alkylaryl; d)—Y—C₁₋₆-alkyl-NR₇R₈; e) —Y—C₁₋₆-alkyl-W—R₂₀; wherein Y and W are,independently selected from the group consisting of —CH₂—, —O—, —N(H),—S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—NHSO₂NH—, —O—CO—,

f) halogen, hydroxyl, cyano, carbamoyl, and carboxyl; wherein R₁₈ andR₁₉ are independently selected from the group consisting of aryl, C₁-C₆alkyl, C₁-C₆ alkylaryl, C₁-C₆ alkoxy, and C₁-C₆ alkoxyaryl; R₂₀ isselected from the group consisting of aryl, C₁-C₆ alkyl, and C₁-C₆alkylaryl; R₇, R₈, R₉ and R₁₀ are independently selected from the groupconsisting of hydrogen, aryl, C₁-C₆ alkyl, and C₁-C₆ alkylaryl; andwherein R₇ and R₈ may be taken together to form a ring having theformula —(CH₂)_(n)—X—(CH₂)_(n)— bonded to the nitrogen atom to which R₇and R₈ are attached, wherein m and n are, independently, 1, 2, 3, or 4;X is selected from the group consisting of —CH₂—, —O—, —S—, —S(O₂)—,—C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,—O—C(O)—, —NHSO₂NH—,

or a pharmaceutically acceptable salt thereof, wherein at least one ofAryl₁ and Aryl₂ is substituted with a lipophilic group of the formula—Y—C₁₋₆-alkyl-NR₇R₈; in combination with one or more therapeutic agentsselected from the group consisting of alkylating agents,antimetabolites, plant alkaloids, antibiotics, hormones, biologicresponse modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids,sulfonylureas, biguanides, insulin, cholinesterase inhibitors,antipsychotics, antidepressants, and anticonvulsants.